1. Field of the Invention
This invention is directed to methods of preparing 4-substituted quinoline compounds as intermediates in the manufacture of receptor tyrosine kinase inhibitors and intermediate compounds used in the methods thereof.
2. Related Background Art
Protein tyrosine kinases (PTKs) are critical in regulating cell growth and differentiation. One general class of PTK is the receptor tyrosine kinase (RTK). Once activated, usually through the binding of a ligand, an RTK initiates signaling for various activities, such as cell growth and replication.
The RTKs comprise one of the larger families of PTKs and have diverse biological activity. At present, at least nineteen (19) distinct subfamilies of RTKs have been identified. One such subfamily is the “HER” family of RTKs, which includes epidermal growth factor receptor (EGFR), ErbB2 (HER2), ErbB3 (HER3) and ErbB4 (HER4).
Under certain conditions, as a result of either mutation or over expression, studies have shown that these RTKs can become deregulated; the result of which is uncontrolled cell proliferation which can lead to tumor growth and cancer (Wilks, A. F., Adv. Cancer Res., 60, 43 (1993) and Parsons, J. T.; Parsons, S. J., Important Advances in Oncology, DeVita, V. T. Ed., J. B. Lippincott Co., Phila., 3 (1993)). For example, over expression of the receptor kinase product of the ErbB2 oncogene has been associated with human breast and ovarian cancers (Slamon, D. J. et al., Science, 244, 707 (1989) and Science, 235, 177 (1987)).
In addition, deregulation of EGFR kinase has been associated with epidermoid tumors (Reiss, M., et al., Cancer Res., 51, 6254 (1991)), breast tumors (Macias, A. et al., Anticancer Res., 7, 459 (1987)), and tumors involving other major organs (Gullick, W. J., Brit. Med. Bull., 47, 87 (1991)).
These RTKs are known to also be involved in processes crucial to tumor progression, such as apoptosis, angiogenesis and metastasis.
Therefore, inhibitors of these RTKs have potential therapeutic value for the treatment of cancer and other diseases characterized by uncontrolled or abnormal cell growth. Accordingly, many recent studies have dealt with the development of specific RTK inhibitors as potential anti-cancer therapeutic agents (e.g., Traxler, P., Exp. Opin. Ther. Patents, 8, 1599 (1998) and Bridges, A. J., Emerging Drugs, 3, 279 (1998)).
Quinoline derivatives are known to be important intermediate compounds in the synthesis of RTK inhibitors. For example, in the following US patents, quinoline derivatives are disclosed and the compounds are stated to be involved in inhibiting PTK activity: U.S. Pat. No. 6,288,082 (Sep. 11, 2001) and U.S. Pat. No. 6,297,258 (Oct. 2, 2001).
In addition, various methods for the preparation of quinoline derivatives are known in the art, but these methods contain serious limitations. One such method is the thermal cyclization reaction. (Sabnis, R. W., et al., J. Hetero. Chem., 29, 65 (1992); Mehta, N. C., et al., J. Ind. Chem. Soc., 55(2), 193 (1978); Bredereck, H., et al., Chem. Ber., 98(4), 1081 (1965); Salon, J., et al., fur Chem., 131, 293 (2000)). Although commonly used, this method requires high temperature conditions, which limits its use for large-scale production of quinoline and quinoline derivatives. This method also requires high dilution conditions, which results in an overall decrease in throughput. Furthermore, the yields from thermal cyclization reactions are typically 50% or less.
Another limitation is that many reactions used in preparing quinoline derivatives often generate unwanted by-products. For example, the chlorination reaction used in preparing quinoline derivatives suffers from the generation of viscous tars and decomposition products that are difficult to clean and remove, which results in yields that vary widely, typically in the range from 24-64%.
Recently, there has been research into other methods for the preparation of quinoline derivatives. One such method involves the use of microwave-assisted methodology for the preparation of quinolones from aromatic amines. (Dave, C. G., et al., Ind. J. Chem., 41B, 650 (2002)). However, these newer methods also suffer from the same foregoing limitations, such as the high temperature conditions requirement.
Accordingly, there continues to be a need for novel quinoline compounds used in the preparation of RTK inhibitors and methods of preparing such quinoline compounds without the foregoing limitations. In particular, there is a need for methods of preparing such quinoline compounds without the requirement of high temperature conditions.